The present invention relates to new compounds which are useful in the regulation of the interconversion of polyamines. More specifically, the present invention contemplates inhibitors of spermidine/spermine N.sup.1 -acetyltransferase, which plays a key role in regulating the interconversion of polyamines.
Maintenance of normal cellular polyamine concentration is needed for normal cell growth. When polyamine synthesis is prevented, cell growth is retarded, offering an opportunity to study the physiological role of the acetylase/oxidase pathway for the interconversion of polyamines. The inhibitors of polyamine synthesis have considerable potential as therapeutic agents for a wide variety of diseases. These inhibitors have their greatest potential when employed in the treatment of neoplastic diseases and other diseases involving deranged cell growth or as antiparasitic protozoan agents.
Ornithine decarboxylase is the only route to de novo polyamine synthesis in mammalian cells, but these cells are able to redistribute polyamines via the acetylase/oxidase pathway. The rate limiting step in this cellular redistribution is the spermidine/spermine N.sup.1 -acetyltransferase. The present compound is a specific and potent inhibitor of this enzyme, which can be used to prevent the acetylation step and subsequent redistribution of polyamines. This inhibitor, either alone or in combination with other compounds which affect other steps in the polyamine pathway, inhibits the production of specific enzymes in the pathway and therefore has wide potential in the treatment of various diseases.
Mammalian cells are known to contain a number of enzymes that catalyze the acetylation of polyamines and histones. Matsui, et al. (J. Biol. Chem. 256, 2454-2459, 1981) identified inducible spermidine/spermine N.sup.1 -acetyltransferase as an enzyme that catalyzes the acetylation of polyamines and plays a key role in the regulation of polyamine interconversion.
Cullis, et al. ("Inhibition of Histone Acetylation by N-[2-(S-Coenzyme A)Acetyl] Spermidine Amide, A Multisubstrate Analog," J. Bio. Chem., Vol. 257, No. 20, pp. 12165-12169 (1982)) describe a method of synthesis of a multisubstrate analog N-[2-(S-Coenzyme A)acetyl] spermidine amide as a potential histone acetylation inhibitor. This research demonstrated the ability of this analog to inhibit histone acetylation in mammalian cells.
Further work done by Erwin, et al.("Differential Inhibition of History and Polyamine Acetylase by Multisubstrate Analogues," Biochemistry 23(18): pp 4250-4255, 1984) describes a method of synthesis similar to Cullis, et al. According to this study, interconversion of polyamines can be varied in response to exogenous stimuli.
Earlier, Libby, in a publication entitled, "Acetyl Spermidine Deacetylase," Arch. Biochem. Biophys., Vol. 188, p. 360 (1978) described the results of the inhibition of the deacetylase enzyme by various polyamines.
A recent study by Sjoerdsma and Schechter ("Chemotherapeutic Implications of Polyamine Biosynthesis Inhibition," Clin. Pharmacol. Therap., (1983)) discusses the clinical significance of polyamine biosynthesis in such diseases as neoplastic disease, parasitic protozoan caused diseases, diseases involving deranged cell growth and other related diseases. Specifically, the researchers tested the effects of D,L-difluoromethylornithine (DFMO) as an inhibitor of polyamine biosynthesis and its value as a therapeutic agent in various diseases. The results indicated that the therapeutic value of DFMO was minimal, but that an effective inhibitor would possess tremendous potential as a therapeutic agent.